Histiocytic & Mast Cell Disorders
Dendritic cells, macrophages, and mast cells gone rogue
Langerhans Cell Histiocytosis
Nature of the disease. Langerhans cell histiocytosis (LCH) is a clonal myeloid neoplasm of dendritic cells that resemble the Langerhans cells of the epidermis. MAPK pathway activation drives it: BRAF V600E is found in about half of cases and MAP2K1 mutations in many others. Lesional cells have pale cytoplasm and grooved, coffee-bean nuclei and are mixed with abundant eosinophils.
Markers. LCH cells are CD1a+, S-100+, and langerin (CD207)+. On electron microscopy they contain Birbeck granules, rod-shaped cytoplasmic organelles with a tennis-racket profile whose formation depends on langerin.
| Form | Typical patient | Presentation | Outlook |
|---|---|---|---|
| Unifocal (eosinophilic granuloma) | Older children, young adults | Solitary lytic lesion of skull, femur, rib, or vertebra; pain, pathologic fracture | Excellent; curettage, may regress |
| Multifocal (Hand-Schüller-Christian) | Young children | Multiple calvarial lesions, central diabetes insipidus, exophthalmos | Good; full triad in a minority |
| Multisystem (Letterer-Siwe) | Infants <2 years | Seborrheic-like rash, hepatosplenomegaly, lymphadenopathy, lung and marrow disease | Worst, especially with liver, spleen, or marrow involvement |
| Pulmonary LCH | Adult smokers | Upper-lobe nodules and cysts | May regress after quitting smoking |
Bone disease. The eosinophilic granuloma is the most common and most benign form: a punched-out lytic lesion that causes pain, swelling, or a pathologic fracture. A collapsed, wafer-flat vertebral body in a child (vertebra plana) is a classic image.
Endocrine and orbital disease. Infiltration of the hypothalamus and posterior pituitary causes central diabetes insipidus with polyuria, polydipsia, and dilute urine that responds to desmopressin, while orbital masses push the eye forward.
Treatment. Localized bone lesions are curetted. Multisystem disease is treated with vinblastine plus prednisone, and BRAF or MEK inhibitors are used for refractory disease. Involvement of the liver, spleen, or marrow ("risk organs") predicts the worst outcome.
Hemophagocytic Lymphohistiocytosis
Pathogenesis. HLH is a life-threatening hyperinflammatory syndrome. Normally, cytotoxic T cells and NK cells kill infected or activated cells using perforin and granzymes, which removes the antigen and ends the response. When killing fails, antigen persists and the lymphocytes keep secreting IFN-γ, which activates macrophages. The result is a cytokine storm (IFN-γ, TNF-α, IL-6, IL-18), tissue infiltration by lymphocytes and macrophages, and hemophagocytosis, in which macrophages engulf red cells, white cells, and platelets. Multiorgan failure follows if untreated.
Familial HLH. Primary HLH presents in infancy and is autosomal recessive, caused by mutations in PRF1 (perforin) or in genes that release cytotoxic granules (UNC13D, STX11, STXBP2). It also complicates Chédiak-Higashi syndrome, Griscelli syndrome, and X-linked lymphoproliferative disease (SH2D1A/SAP deficiency), which causes fulminant HLH in boys after EBV infection.
Secondary HLH. More common in older children and adults, it is triggered by infection (especially EBV), malignancy (particularly lymphoma), or autoimmune disease; in systemic juvenile idiopathic arthritis and adult Still disease it is called macrophage activation syndrome.
Diagnosis. The HLH-2004 criteria require a known familial mutation or five of these eight findings:
- Fever
- Splenomegaly
- Cytopenias in at least two lineages
- Fasting triglycerides ≥265 mg/dL and/or fibrinogen ≤150 mg/dL
- Ferritin ≥500 ng/mL (values above 10,000 strongly suggest HLH)
- Hemophagocytosis in marrow, spleen, or lymph nodes
- Low or absent NK-cell activity
- Soluble CD25 (IL-2 receptor α) ≥2,400 U/mL
Why the labs look this way. Activated macrophages secrete ferritin; TNF-α suppresses lipoprotein lipase, raising triglycerides; and macrophage plasminogen activator lowers fibrinogen. Transaminases and LDH are also elevated.
Treatment. Dexamethasone plus etoposide (the HLH-94 protocol) suppresses the immune storm, and the trigger is treated, for example with rituximab to remove EBV-infected B cells. The anti-IFN-γ antibody emapalumab is an option in refractory primary HLH, and familial HLH requires allogeneic stem cell transplant.
Systemic Mastocytosis
Pathogenesis. Clonal mast cells carrying the gain-of-function KIT D816V mutation (more than 90% of adults) accumulate in marrow, skin, liver, spleen, lymph nodes, and gut. The marrow shows dense aggregates of spindle-shaped mast cells that are CD117+ and tryptase+ and aberrantly express CD25 and CD2. Serum tryptase is persistently elevated, above 20 ng/mL. D816V lies in the kinase activation loop and prevents imatinib binding; midostaurin, avapritinib, and cladribine are used for advanced disease.
Skin. Maculopapular cutaneous mastocytosis (formerly urticaria pigmentosa) consists of red-brown macules and papules that swell, redden, and itch when rubbed. This Darier sign reflects mechanical degranulation of dense dermal mast cells. Childhood cutaneous mastocytosis often regresses by adolescence, whereas adult-onset disease is usually systemic.
Mediator symptoms. Histamine acting on H1 receptors causes flushing, pruritus, urticaria, and hypotension, which can progress to anaphylaxis; prostaglandin D2 adds flushing and wheezing. Histamine acting on parietal cell H2 receptors drives gastric acid hypersecretion, peptic ulcers, and diarrhea. Mast cell products also promote osteoporosis and vertebral fractures.
Management. H1 plus H2 blockers, oral cromolyn (a mast cell stabilizer), and an epinephrine autoinjector control symptoms. Patients avoid degranulation triggers: insect stings, alcohol, NSAIDs, opioids, and sudden temperature changes.
Buzzword map: Birbeck granules and CD1a = LCH; extreme ferritin with low fibrinogen = HLH; Darier sign with high tryptase = mastocytosis.